PROJECT SUMMARY/ABSTRACT Despite advances in both pharmacotherapy and psychotherapy for major depression, non-response and partial-response remain relatively common outcomes, motivating the search for new treatments. This application is concerned with the development of one such novel treatment, based on one of the particular successes of translational research: the augmentation of exposure-based cognitive-behavior therapy (CBT) with d-cycloserine (DCS). In this application, we propose a study of the efficacy of DCS for augmenting therapeutic learning relevant for the treatment of depression (i.e., outside the extinction learning where DCS has been shown to have success). Specifically, appropriate to an R-21 mechanism (PA-11-261), we investigate the role of DCS in enhancing declarative memory in depressed individuals, as evaluated by standardized tests and the retention of cognitive therapy session material. In seeking to extend the therapeutic targets for DCS augmentation, we are also proposing to study an active comparison agent. This agent, modafinil, appears to offer cognitive enhancing effects among both sleep deprived and non-sleep deprived individuals, but also appears to have drug-state (e.g., mood and side) effects that are not characteristic of DCS augmentation. For this reason, drug-context effects may affect memory retention over time. Hence, we will evaluate memory enhancement effects both during the period of drug action as well as one week later when no drug is taken. Overall, we propose to examine cognitive function and memory performance over 4 study sessions in 96 men and women with major depression, who, in a double-blind fashion, will be randomly assigned to either: (1) 50mg DCS, (2) 250mg DCS, (3) 100mg modafinil, or (4) placebo administered on Study Weeks 2 and 3. The memory tests include both items unique to a given study week (i.e., item categorization, the HVLT, and digits backward), and memory tasks that are repeated over time (logical memory tasks and the cognitive therapy content), that allow assessment of memory and retention effects across one-week periods (i.e., from Week 2 to Week 3 and from Week 3 to Week 4). We believe this study is the next logical step toward the goal of extending CBT augmentation effects for depression. If study aims are achieved in this R21 study, we will proceed with a R01 application at the conclusion of the funding period, working to show whether augmentation of therapeutic learning leads to an earlier and/or more robust treatment response for depressed patients undergoing CBT.